The overall objective of the proposed research is to develop new, efficient organic synthetic methods using transition metal reagents and to apply these new methods to the synthesis of biologically active compounds. The new methods will be developed to meet several important criteria, including simplicity, generality, flexibility and high stereoselectivity. Each of these criteria is critical, both to the ultimate applicability of the methodology to the synthesis of specific (as opposed to "model") biologically active compounds, and to the overall utility of the new methodology to the evolution and study of new drugs, a process which involves systematic structure variation and extensive structure-activity relationship studies. Methodology, to synthesize several major classes of optically active, biologically active compounds will be developed. These are: (1) natural and unnatural alpha-amino acids including multiply labelled compounds for metabolism studies, and alpha, alpha-dialkylamino acids; (2) small peptides with strategically located unnatural and/or labelled amino acids produced as above; (3) various hydroxy amino acids as components for renin inhibitors; (4) functionalized azapenams, diazepinones, and macrocyclic polyamine chelate compounds (cyclams) having several chiral centers, new classes of compounds unavailable by conventional methodology. The methodology, will be applied to sufficiently, complex target molecules to convince both us ;and the synthetic/biological community at large that it is indeed applicable to and useful for 'real" systems, and will be published, as is our custom, will full experimental details immediately upon its completion. A major portion of the proposed research deals with the development of photolytic reactions of chromium carbene complexes to produce optically active natural, unnatural, and multiply labelled alpha-amino acids, and to permit their direct incorporation into peptides. This is an area of great current interest and activity because this class of compounds has become central to a wide range of biologically active compounds, particularly enzyme inhibitors, hormones, synthetic immunostimulants and antibiotics. Their specific incorporation into small peptides use as agonists, and antagonists for biologically active peptides and for the production of analogs for structure/activity studies is central to a very large area of modern drug design. The proposed research in this area is significant because it will permit the synthesis of optically active, biological active natural and unnatural amino acids under exceptionally mild conditions (visible light, any solvent) and will permit their direct incorporation into peptides without the use of any external reagents; processes unprecedented in conventional organic synthesis. Further, it will permit the facile synthesis and incorporation into peptides of multiply 13C labelled, stereospecifically deuterated or tritrated alpha-amino acids, for use in metabolic studies. This ability is simply unavailable using conventional methodology.